The use of controlled-release compositions (also known as slow-release, sustained-release, or extended-release) is well established in medicine. Controlled-release formulations have the advantage that the active drug is gradually released over a relatively long period so that the drug is maintained in the blood stream for a longer time and at a more uniform concentration than would otherwise be the case. This allows administration only once or ice daily for drugs that would otherwise have to be taken more frequently to maintain required blood levels.
Many different types of controlled-release oral dosage forms have been developed, but each has disadvantages which affect its suitability to a particular drug and therapeutic objective.
The prior art discloses many compositions which incorporate the drug into a water-insoluble matrix, from which the drug will be slowly released in gastrointestinal fluid.
In the process of British Patent No. 1021924, the drug is admixed with a sustained-release material to obtain a mixture which is subsequently pressed into tablets. The sustained release material is used in amounts of as much as 95%, which results in substantial cost for this material and also produces a tablet larger than otherwise required.
British Patent No. 1137379 discloses use of ethylcellulose as a water-insoluble binder. The ethylcellulose is dissolved in alcohol and the solution is mixed with the drug in a multistep process. The alcohol must be evaporated, and the process is complex and not economical.
U.S. Pat. No. 2809916 also discloses a formulation process using repeated steps of mixing a drug with a water-insoluble excipient, drying and granulating.
In other prior art compositions the drug is incorporated into a matrix that is water-soluble but dissolves away only slowly to release the drug. The use of hydrophilic polymers such as hydroxypropylmethylcellulose as sustained-release matrix materials is well-known.
For example, U.S. Pat. Nos. 3065143 and 4369112 disclose the use of hydrophilic gums, including hydroxypropylmethylcellulose, as carrier base materials in the preparation of sustained-release pharmaceutical tablets.
As aforesaid, controlled-release tablets can be made by incorporating the drug into a matrix that is either water-insoluble or slowly water-soluble. However, in either case there are difficulties in achieving a uniform rate of release.
If the matrix is water-insoluble, the drug tends to be initially released relatively rapidly as the drug near the surface leaches out, and the rate of drug release then gradually reduces.
If the matrix is water-soluble, the layer at the surface gradually dissolves to expose more drug, so that the rate of release is more uniform over time than with a water-insoluble matrix. However, compositions of this type tend to suffer from "food effect". That is to say, release rate tends to be higher when the tablet is taken with food then without. This is because, with food, the gastrointestinal motility is higher and the increased agitation causes the tablet to dissolve away more rapidly.
It is possible to obtain rates of release that are more consistent using a "multi-granular" composition, by which is meant a composition that is comprised of and disintegrates in gastrointestinal fluid into a multitude of smaller individual granules, pellets, beads or tablets, each of which is itself a controlled-release composition.
For example, U.S. Pat. No. 5286497 discloses controlled-release compositions of diltiazem hydrochloride which are comprised of a multitude of beads which are contained with a gelatin capsule. However, such compositions are difficult and expensive to produce.
Drugs with low solubility in water (by which is meant having a solubility of less than 0.1 percent by weight in water at 20.degree. C.) cause additional formulation problems due to their poor rate and extent of dissolution in aqueous media (including gastrointestinal fluids), which results in low absorption into systemic circulation after oral ingestion.
Examples of drugs with low solubility in water are some substituted dihydropyridine compounds, such as nifedipine, felodipine, nimodipine, isradipine, nitrendipine, nicardipine, niludipine, nisoldipine, and amlodipine. These compounds are classified as calcium antagonists, which are widely used for the treatment of cardiovascular disorders such as hypertension.
In order to make a controlled-release composition containing such a drug that will enable maximum absorption from the gastrointestinal tract, in addition to incorporating a feature to control the rate of release, it is necessary to incorporate in the composition a second feature that increases the solubility of the drug to enable it to dissolve in the gastrointestinal fluids.
Several ways to increase the solubility have been described in prior literature. One way is described in U.S. Pat. No. 4673564, wherein nicardipine is used in its amorphous form in order to obtain increased dissolution and absorption. U.K. I 456618 discloses improving the dissolution and absorption of nifedipine by preparation of a solid solution of nifedipine in polyethylene glycol in the presence of a surface active agent.
U.S. Pat. No. 4412986 discloses improving the dissolution and absorption of nifedipine by preparing a co-precipitate with a water-soluble polymer.
As aforesaid, in order to produce a controlled-release composition of a drug having low solubility in water, it is necessary to have one feature to increase the solubility and a second feature to slow down and control the rate of dissolution.
The prior art also discloses numerous compositions which include a feature of each type to achieve controlled-release of a drug having low solubility in water.
European patent application 0557-244-Al discloses compositions which contain nifedipine which has been micronized to small crystals to increase solubility, along with a hydrophilic gel-forming polymer to slow-down and control the rate of dissolution and absorption. A problem with the compositions disclosed in this patent is that the smallest size to which nifedipine can be micronized using conventional equipment is about 1 micron, and this particle size is still not small enough to enable full dissolution and absorption of the nifedipine. Moreover, unless the crystal size is carefully controlled-to be the same in every batch of tablets, release characteristics may vary from batch to batch. Another problem is that, as aforesaid, the use of a hydrophilic polymer as the agent to control rate of release causes the composition to be subject to a "food effect".
New Zealand patent application No. 270439 discloses a controlled-release tablet in which nifedipine is dissolved in a molten polyethylene glycol and which further incorporates a hydrophilic polymer. Again, the use of a hydrophilic polymer causes the composition to be subject to a "food effect".
U.S. Pat. No. 4765989 discloses a controlled-release formulation of nifedipine in the form of an osmotic device, which gives a reliable and uniform rate of release, but is relatively difficult and expensive to manufacture.
In view of the difficulties as aforesaid with prior art compositions, it is an object of the invention to enable production of a controlled-release composition which can be easily made, without the use of solvents that require evaporation in the process of manufacture, and, in particular, to enable such a composition for a drug having low solubility in water.